Levels of chromium in the U.S. diet may be less than optimal for certain individuals and marginal deficiency states may exist particularly in pregnancy and old age (Recommended Dietary Allowances, 9th edition, National Academy of Sciences). Chromium compounds which are physiologically available, safe and stable would be useful to enrich and fortify foods, or for use as a dietary supplement.
Diabetes is an ongoing problem which has only been partially controlled by the use of insulin therapy and dietary adjustments. There are two principal forms of diabetes. Diabetics who suffer from insulin-dependent-diabetes mellitus (IDDM) fail to produce adequate amounts of insulin. IDDM diabetics comprise about 10% of the total population of diabetics. Non-insulin-dependent-diabetes mellitus (NIDDM) diabetics do produce insulin, often 2-3 times normal amounts, but fail to adequately utilize insulin. This failure in utilizing the body's own insulin is termed insulin resistance. Roughly 90% of all diabetics have insulin resistance. It is recognized that insulin resistance and an attendant hyperinsulinemia are associated with a host of diseases including obesity, hypertension, coronary artery disease, hyperlipidemia and Cushing's syndrome as well as NIDDM diabetes.
Compounds which significantly potentiate (compounds which reduce insulin resistance and thereby augment insulin action are referred to herein as "potentiators") insulin action, at times referred to herein as having GTF-like activity, if available, would be useful in treating insulin resistance and would be potentially useful in treating insulin resistance diseases depending upon the degree which insulin resistance contributes to the overall pathophysiology. Such compounds would, if available, be useful in the treatment of IDDM diabetics who are also insulin resistant. The amount of supplemental insulin normally prescribed for such diabetics could be significantly reduced.
It has been known for some time that extracts of yeast and other natural products include GTF which is a compound or mixture of compounds, along with impurities. GTF has been postulated to be an effective factor in aiding NIDDM diabetics. Its precise structure, or even whether it is one compound or a mixture of compounds, is the subject of conjecture but is not known. Workers in the field have developed data which indicate that GTF includes one or more nicotinic acid moieties, chromium, and certain amino acids (glutamic acid, cysteine and glycine) corresponding to those in glutathione; Toepfer, Z. W., J. Agric. Food Chem. 25, No. 1, 162-66 (1977). From these partial data it has been postulated by Mertz that glutathione may be one of the moieties forming GTF. Pure, or even nearly pure, GTF has not previously been synthesized and its exact structure is not known.
Over the years a number of attempts have been made to synthesize GTF and a number of compounds having at least some GTF-like activity have been reported. Indeed, some of the compounds reported in the literature have been incorrectly postulated as probably containing two nitrogen-bound nicotinic acid moieties per one chromium atom. Such results are presented, for example, by Anderson, et al, J. Agric. Food Chem. Vol. 26, No. 5, 1978 at pages 1219-1221. Anderson, et al also mention a chromium-nicotinic acid-glutathione material as having GTF-like activity in Federation Proceedings 36, 1977, as reported on page 11 in Abstract No. 4507. Polyhedron Report No. 9, Polyhedron Vol. 4, No. 1, pages 1-14, 1985, discusses the Anderson, et al result on pages 3-5. And, a number of postulated but unproven structures for GTF appear later in this article. Also, in Trace Element Metabolism in Man and Animals-3, Proceedings of the 3rd International Symposium, Freising, Fed. Rep. of Germany, July 1977, particularly on page 272 thereof, in an article by Mertz, et al, a discussion of a possible structure of GTF is set forth. Still further, in Chromium in Nutrition and Disease, G. Saner, Alan R. Liss, Inc., Publisher, New York, N.Y., 1980, particularly on page 9 thereof, a discussion is set forth relating to tetra-aquo-di-nicotinato chromium complexes.
The prior art attempts to synthesize GTF and GTF-like compounds have been concerned with reacting Cr(III) salts with such materials as nicotinic acid and glutathione (or select amino acids). As a result, the prior art, as is shown experimentally below, has not succeeded in forming Cr(III), nicotinic acid, glutathione (or amino acid) compounds wherein the Cr(III) has been attached to the nicotinic acid moiety via the nitrogen in the aromatic nitrogen containing (pyridine) ring.
With all of the above theories and all of the prior attempts to synthesize GTF and GTF-like compounds, none of the synthesized compounds has the effectiveness of, nor the structure of, GTF itself. The synthesis of GTF, or of compounds having comparable GTF-like activity to GTF, would be very beneficial in that such compounds could then be produced in quantity and be utilized to treat insulin resistance-related disorders.
It has been observed (Doisy, et al, Excerpta Medica, Int. Cong. Series, 280, 155 Abstracts, 1973) that injecting db/db mice with yeast extracts containing high GTF can delay the spontaneous degeneration of the insulin-producing beta cells of the pancreas. Therefore, there may also be a use of GTF-like compounds for treating IDDM diabetes.
The present invention is directed to overcoming one or more of the problems as set forth above.